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Volume 24, Issue 3 (May 2022) 24, 248–254; 10.4103/aja2021106

Investigation of the genetic etiology in male infertility with apparently balanced chromosomal structural rearrangements by genome sequencing

Matthew Hoi Kin Chau1,2,3, Ying Li1,2, Peng Dai4, Mengmeng Shi1,2, Xiaofan Zhu4, Jacqueline Pui Wah Chung1, Yvonne K Kwok1,2, Kwong Wai Choy1,2,3,5, Xiangdong Kong4, Zirui Dong1,2,3

1 Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
2 Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China
3 Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
4 Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
5 The Chinese University of Hong Kong-Baylor College of Medicine Joint Center for Medical Genetics, Hong Kong, China

Correspondence: Dr. Z Dong (elvisdong@cuhk.edu.hk)

Date of Submission 28-Jul-2021 Date of Acceptance 27-Oct-2021 Date of Web Publication 07-Jan-2022


Apparently balanced chromosomal structural rearrangements are known to cause male infertility and account for approximately 1% of azoospermia or severe oligospermia. However, the underlying mechanisms of pathogenesis and etiologies are still largely unknown. Herein, we investigated apparently balanced interchromosomal structural rearrangements in six cases with azoospermia/severe oligospermia to comprehensively identify and delineate cryptic structural rearrangements and the related copy number variants. In addition, high read-depth genome sequencing (GS) (30-fold) was performed to investigate point mutations causative of male infertility. Mate-pair GS (4-fold) revealed additional structural rearrangements and/or copy number changes in 5 of 6 cases and detected a total of 48 rearrangements. Overall, the breakpoints caused truncations of 30 RefSeq genes, five of which were associated with spermatogenesis. Furthermore, the breakpoints disrupted 43 topological-associated domains. Direct disruptions or potential dysregulations of genes, which play potential roles in male germ cell development, apoptosis, and spermatogenesis, were found in all cases (n = 6). In addition, high read-depth GS detected dual molecular findings in case MI6, involving a complex rearrangement and two point mutations in the gene DNAH1. Overall, our study provided the molecular characteristics of apparently balanced interchromosomal structural rearrangements in patients with male infertility. We demonstrated the complexity of chromosomal structural rearrangements, potential gene disruptions/dysregulation and single-gene mutations could be the contributing mechanisms underlie male infertility.

Keywords: azoospermia; balanced structural rearrangements; genome sequencing; male infertility; severe oligospermia

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Asian Journal of Andrology CN 31-1795/R ISSN 1008-682X  Copyright © 2023  Shanghai Materia Medica, Chinese Academy of Sciences.  All rights reserved.